The present invention relates to a new method for the preparation of Ceftiofur acid of formula (I): 
and its pharmaceutically acceptable salt such as sodium or hydrochloride.
The present invention also provides two new intermediates of formulae (V) and (VI): 
wherein X represents halogen atom such as chlorine or bromine, R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group.
Ceftiofur acid, its alkali metal, alkaline earth metal and amines salts were reported for the first time in U.S. Pat. No. 4,464,367. During the course of further investigation, later on, it was discovered that all these derivatives of Ceftiofur are known to have stability problems. Further, it was difficult to purify the derivative of Ceftiofur due to amorphous nature of the compound. In fact, from the beginning, preparation of Ceftiofur sodium has posed challenges to organic chemists regarding purity, stability and crystallinity.
Several attempts have been made to prepare Ceftiofur sodium for obviating above-mentioned problems. One of the solutions was provided in U.S. Pat. No. 4,877,782 by preparing zinc complexes of Ceftiofur which have better dispersibility in water and can be used in pharmacological preparations. U.S. Pat. No. 4,902,683 also explains the isolation of more stable Ceftiofur in the form of crystalline hydrohalide salts which has better solubility and other physical properties, as compared to parent compounds. During the isolation of Ceftiofur hydrochloride salt most of the impurities present in the compound are removed during filtration. The hydrohalide salts as such cannot be used for parenteral administration, therefore it is necessary to convert a hydrohalide salt to sodium salt in order to use the drug as injectable.
EP 0030294 discloses the condensation of the 4-halogeno-2-substitutedimino-3-oxo-butyric acid with cephem carboxylic acids by using PCl5 Another EP patent 0 842 937 discloses the formation of amide bond with cephem moiety by reacting with the thioester derivative of 4-chloro-2-methoxyimino-3-oxo-butyric acid. The thioester was prepared by reacting 4-chloro-2-methoxyimino-3-oxo-butyric acid with 2,2xe2x80x2-dithio-bis-benzothiazole in the presence of triphenyl phosphine which is costly material and its by product triphenyl phosphine oxide is also difficult to remove from the reaction mixture.
The primary objective of the invention is to provide a new method for the preparation of Ceftiofur acid of formula (I), which would be easy to implement in commercial scales.
Another objective of the present invention is to provide the novel intermediates of formulae (V) and (VI), which are useful in the preparation of Ceftiofur derivatives.
Another objective of the present invention is to provide a process for the preparation of intermediates of the general formulae (V) and (VI), in good yields with high purity.
In accordance, the present invention provides a new method for the preparation of ceftiofur acid of formula (I) and its pharmaceutically acceptable salt such as sodium or hydrochloride and also provides two intermediates of formulae (V) and (VI).
Accordingly, the present invention provides a method for the preparation of Ceftiofur acid of formula (I): 
and its pharmaceutically acceptable salt such as sodium or hydrochloride, which comprises the steps of:
(i) condensing an activated derivative of formula (III) where X represents halogen atom such as chlorine or bromine, with silylated derivative of 7-amino cephalosporin of formula (IV) wherein R is as defined earlier in the presence of a solvent at a temperature in the range of xe2x88x9240xc2x0 C. to 0xc2x0 C. to produce a compound of formula (V), where R is as defined earlier,
(ii) cyclising the compound of formula (V) with thiourea in the presence of water miscible solvent and sodium acetate at room temperature to produce cephalosporin compounds of formula (VI) wherein R is as defined earlier,
(iii) deesterifying the compound of formula (VI) using anisole/trifluroacetic acid, phenol/trifluroacetic acid or formic acid in the presence or absence of a solvent at a temperature in the range of 0xc2x0 C. to 10xc2x0 C. to produce a compound of formula (I) and, if desired,
(iv) converting the compound of formula (I) to its pharmaceutically acceptable salt.
The process is as shown in Scheme-1 below: 
In another embodiment of the present invention, there is provided a new intermediate of formula (V): 
wherein X represents halogen atom such as chlorine or bromine, R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group.
In yet another embodiment of the present invention, there is provided a new intermediate of formula (VI): 
wherein R represents p-methoxybenzyl, p-nitrobenzyl or diphenylmethyl group.
In still another embodiment of the present invention the compound of formula (IV) can be prepared by a process which comprises protecting the compound of formula (VII) using p-methoxybenzyl halide, p-nitrobenzyl halide, or diphenylmethane halide or diphenyldiazomethane, in the presence of a solvent and base.
The process is as shown in Scheme-2 below 
In still another embodiment of the present invention, there is provided an alternate process for the preparation of a compound of formula (IV), which comprises:
(i) condensing the 7-aminocephalosporin derivative of formula (VIII) wherein R1 represents hydrogen, (C1-C4)alkyl, substituted or unsubstituted phenyl or substituted or unsubstituted phenoxy with furyl-2-carbonylthiol of formula (IX) in the presence in an organic solvent and a base at a temperature in the range of 0xc2x0 C. to 30xc2x0 C. to produce 7-aminocephalosporin derivative of formula (X),
(ii) removing the acetyl group on the N-atom in the 7-aminocephalosporin derivative of formula (X) using PCl5/POCl3/pyridine, PCl5/pyridine or triphenyl phosphite/Cl2 complexes in the presence of an alcohol, at a temperature in the range of xe2x88x9240xc2x0 C. to 0xc2x0 C. to produce the compound of formula (IV), and
(iii) isolating the compound of formula (IV).
The process is shown in Scheme-3 below 
In yet another embodiment of the present invention, a the condensation in step (i) is performed by using the activated compound of formula (III) in the presence of a solvent selected from dichloromethane, ethyl acetate, tetrahydrofuran, aromatic hydrocarbon, acetone, dioxane, acetonitrile, N,N-dimethylformamide, dialkylethers, water or mixtures thereof.
The compound of formula (III) is activated as acid halides, mixed anhydrides, active esters, and active amides. The acid halides are acid chlorides or acid bromides. The mixed anhydrides are anhydrides of the compounds of formula (III) with pivaloyl chloride, ethyl chloroformate, benzyl chloroformate.
In yet another embodiment of the present invention the cyclisation in step (ii) is carried out using a mixture of water and organic solvent selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3) alcohol or mixtures thereof.
In still another embodiment of the present invention, the deesterification in step (iii) is carried out using anisole/trifluoroacetic acid, phenol/trifluoroacetic acid or formic acid in the absence or presence of dichloromethane as a solvent. In another embodiment of the present invention, the pharmaceutically acceptable salt is sodium or hydrochloride.
In another embodiment of the present invention, the solvent used in scheme-2 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza-bicyclo[5,4,0]-undec-7-ene (DBU), pyridine or sodium carbonate.
In another embodiment of the present invention, the solvent used in step (i) of scheme-3 is selected from tetrahydrofuran, acetone, acetonitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dioxane, (C1-C3)alcohol or mixtures thereof, in the presence of a base selected from sodium acetate, potassium carbonate, triethylamine, 1,4-diazabicyclo-[2,2,2]-octane (DABCO), 1,5-diazabicyclo[4,3,0]-non-5-ene (DBN), 1,8-diaza-bicyclo[5,4,0]-undec-7-ene (DBU), pyridine or sodium carbonate.
The compound of formula (IX) used in step (i) of scheme-3 is freshly prepared from furoyl chloride and sodium sulphide in a mixture of water and solvent selected from ethyl acetate or dichloromethane.
The substituents on R1 in Scheme-3 are selected from methyl, methoxy, nitro, and halogen atom.
The present invention is provided by the examples below, which are provided by way of illustration only and should not be considered to limit the scope of the invention.